Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner

Nethisinghe, Suran; Kesavan, Maheswaran; Ging, Heather; Labrum, Robyn; Polke, James M.; Islam, Saiful; García-Moreno, Héctor; Callaghan, Martina F.; Cavalcanti, Francesca; Pook, Mark A.; Giunti, Paola

doi:10.3390/ijms22147507

Cited by 15 publications

(11 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The length of the shorter GAA-repeat has been shown to correlate inversely with the age of onset 10 , 26 . We have confirmed this in our data (Supplementary Fig 6 ) and shown that this correlation improves when removing patients with interruptions in the short GAA repeat length 40 . We cross-sectionally predicted the FXN mRNA levels of the participants using four sets of predictors: 8-MW suit features, 9-HPT suit features, SARA and SCAFI, and the results for the leave-one-subject-out cross-validation are presented in Fig.…”

Section: Resultssupporting

confidence: 86%

See 1 more Smart Citation

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Kadirvelu

Gavriel

Nageshwaran

et al. 2023

Nat Med

Self Cite

View full text Add to dashboard Cite

Friedreichʼs ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.

show abstract

Section: Resultssupporting

confidence: 86%

“…Triplet repeat (TP) PCR assays were used to examine interruptions at the 5′ and 3′ ends of the FXN GAA repeat tract independently 40 .…”

Section: Methodsmentioning

confidence: 99%

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Kadirvelu

Gavriel

Nageshwaran

et al. 2023

Nat Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…The higher concordance with the repeat number detected with fast base-calling could result from general repeat number detection of fragment analysis without the resolution of mismatches in the repeat motif. In fact, there was a noticeable increase in the frequency of deletions in the long-read data that require further exploration as interruption of the repeat motif has also been reported for other repeat expansion diseases such as Friedreich’s Ataxia or Huntington disease [ 20 , 21 ]. Therefore, further investigation of this issue, including single nucleotide resolution of the repeat interruption, is required.…”

Section: Discussionmentioning

confidence: 88%

Elucidating Hexanucleotide Repeat Number and Methylation within the X-Linked Dystonia-Parkinsonism (XDP)-Related SVA Retrotransposon in TAF1 with Nanopore Sequencing

Lüth

Laβ

Schaake

et al. 2022

Genes

View full text Add to dashboard Cite

Background: X-linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by progressive dystonia and parkinsonism. It is caused by a SINE-VNTR-Alu (SVA) retrotransposon insertion in the TAF1 gene with a polymorphic (CCCTCT)n domain that acts as a genetic modifier of disease onset and expressivity. Methods: Herein, we used Nanopore sequencing to investigate SVA genetic variability and methylation. We used blood-derived DNA from 96 XDP patients for amplicon-based deep Nanopore sequencing and validated it with fragment analysis which was performed using fluorescence-based PCR. To detect methylation from blood- and brain-derived DNA, we used a Cas9-targeted approach. Results: High concordance was observed for hexanucleotide repeat numbers detected with Nanopore sequencing and fragment analysis. Within the SVA locus, there was no difference in genetic variability other than variations of the repeat motif between patients. We detected high CpG methylation frequency (MF) of the SVA and flanking regions (mean MF = 0.94, SD = ±0.12). Our preliminary results suggest only subtle differences between the XDP patient and the control in predicted enhancer sites directly flanking the SVA locus. Conclusions: Nanopore sequencing can reliably detect SVA hexanucleotide repeat numbers, methylation and, lastly, variation in the repeat motif.

show abstract

“…Repeat interruptions exist in other repeat expansion disorders. 12–15 For example, interruptions with the same motif length, but varying repeat sequence from the canonical repeat motif, have been observed in fragile X syndrome (FXS), Huntington’s disease, spinal cerebellar ataxia (SCA)1, SCA2, SCA3, SCA8, SCA10, SCA17, SCA31, myotonic dystrophy, and Friedreich’s ataxia. 4 , 16 The presence of these interruptions can modify AAO by years.…”

Section: Discussionmentioning

confidence: 99%

Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset

Jamora

Lüth

Schaake

et al. 2022

Brain

View full text Add to dashboard Cite

While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with an expanded (AGAGGG)n. Repeat length and variants in MSH3 and PMS2, explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read Nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5’-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5’-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5’-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42-0.43) and 0.128 (IQR: 0.12-0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate=-3.8342, p = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, p = 0.0441) but not AAO (estimate=-41.486, p = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate=-161.09, p = 3.44 × 10−5). When including the XDP-relevant MSH3/PMS2 modifier SNPs into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, p = 0.047), however, the association dissipated after including the repeat number (estimate=-92.46430, p = 0.079). We reveal novel mosaic Divergent Repeat Interruptions affecting both motif Length and Sequence (DRILS) of the canonical motif polarized within the expanded SINE-VNTR-Alu(AGAGGG)n repeat of TAF1. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.

show abstract

Interruptions of the FXN GAA Repeat Tract Delay the Age at Onset of Friedreich’s Ataxia in a Location Dependent Manner

Cited by 15 publications

References 34 publications

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Elucidating Hexanucleotide Repeat Number and Methylation within the X-Linked Dystonia-Parkinsonism (XDP)-Related SVA Retrotransposon in TAF1 with Nanopore Sequencing

Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset

Contact Info

Product

Resources

About